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What Myriad means for biotech

August 2013

By Emma Barraclough, Group Editor, Managing Intellectual Property

Who owns your genes? Do you own them if they are inside your body, but someone else can own them if they have been removed? Are isolated human genes man-made, patentable inventions or unpatentable products of nature? These were the issues before the nine justices of America's highest court in Association for Molecular Pathology v Myriad Genetics earlier this year.

The story of Myriad begins almost 20 years ago, when Salt Lake City-based Myriad Genetics announced it had sequenced the BRCA1 gene, a mutation that can lead to breast and ovarian cancer. Two years later, the team published the sequence for another gene correlated with hereditary breast and ovarian cancer: BRCA2. It obtained patents on both genes. Its discoveries were lucrative: in 1996 it began selling the first molecular diagnostic test for these hereditary cancers at a cost of around US$3,000 per patient.

Key biotech cases

Judges and patent office officials on both sides of the Atlantic have decided a series of high-profile gene-related disputes. Here are some of the most important.

Diamond v Chakrabarty

In 1980, the Supreme Court of the United States ruled that a micro-organism that had been genetically modified for use in cleaning oil spills was patentable on the grounds that it did not constitute a "product of nature ". The Court set an important precedent in the area of patentability by ruling: "The laws of nature, physical phenomena, and abstract ideas have been held not patentable. Thus, a new mineral discovered in the earth or a new plant found in the wild is not patentable subject matter … Such discoveries are ‘manifestations of . . . nature, free to all men and reserved exclusively to none'. " The decision was a close-run thing, however: four justices dissented, a portent of litigation to come.

Harvard Oncomouse

In 1984, the European Patent Office (EPO) received its first application for a patent of an animal: the genetically modified Harvard Oncomouse. Eight years later it granted a patent to the Harvard University researchers involved, a move opposed by an array of political parties, religious groups and environmental activists. The EPO ultimately upheld the patent in 2004 but ruled that it should relate to transgenic mice only, rather than all rodents.

Prometheus Laboratories, Inc v Mayo Collaborative Services

In March 2012, the Supreme Court ruled that Prometheus' patent claims related to ways of optimizing doses of certain drugs used to treat specific conditions were invalid because they relate to a natural phenomenon. The effect of the decision was to make it harder for developers of genetic tests to obtain patent protection.

Fast-forward to 2009 and the company found itself (along with the Trustees of the University of Utah) sued by a group of human rights campaigners and patients' rights activists. The plaintiffs, who included the Public Patent Foundation (PUBPAT), the American Civil Liberties Union (ACLU) and Breast Cancer Action, challenged claims in seven of Myriad's BRCA patents. Although thousands of genes are patented in the US, PUBPAT attorney Dan Ravicher says the groups targeted Myriad because of the company's reluctance to license its patents to competitors.

Photo: Breakthrough Breast CancerImage of the BRCA gene (above). In the case involving Association for Molecular Pathology v Myriad Genetics the US Supreme Court addressed the issue of whether isolated human genes are patentable. In a unanimous decision, the nine presiding justices ruled that naturally isolated DNA is not patentable but that synthetic DNA, such as cDNA, is patentable.

The plaintiffs prevailed at first instance, when a New York judge held that DNA is un-patentable subject matter. A quirk of timing saw the Federal Circuit for the Court of Appeals consider the dispute twice: once before and once after the Supreme Court ruled in another highly-anticipated biotech case - Prometheus v Mayo - that Prometheus's diagnostic method patents were invalid (See US courts grapple with patent-eligible subject matter).

By the time the Myriad case wound its way up to the Supreme Court, it had attracted almost 50 amicus briefs, from associations of IP lawyers and biotech researchers to venture capitalists and concerned citizens. The interest the case provoked is unsurprising considering both the issues before the Court and trends within the pharmaceutical industry. The dispute raises emotive issues relating to the ownership and control of genetic material just as pharmaceutical companies are desperate to obtain patent rights over medical innovations as the flow of blockbuster drugs dries up. The Court was asked to rule just as personalized medicine, offered via tests such as Myriad's BRACAnalysis, heralds a breakthrough in the delivery of healthcare but also as healthcare budgets come under greater financial pressure than ever.

The question before the Court was whether isolated human genes are patentable

The Supreme Court's nine justices took eight weeks to answer after hearing from both sides in the dispute. What they said was this: a naturally occurring DNA segment is a product of nature and, as such, cannot be patented. In contrast, so-called complementary DNA - an artificial product designed to mirror the coding parts of genes - is eligible for patent protection because it is not naturally occurring. "The lab technician unquestionably creates something new when cDNA is made," they said. The impact on would-be gene patent holders was clear: within hours, the USPTO issued a memo to its examiners instructing them to reject product claims drawn solely to naturally occurring nucleic acids, or fragments of them, whether isolated or not.

The Court's opinion, drafted by Justice Thomas, ran to just 18 pages. Its brevity was interpreted by some as a sign of the open-and-shut nature of the case; by others as evidence of the Court's failure to get to grips with the difficult issues raised by the dispute. There were complaints that the case-specific ruling offered little guidance as to how the law should be applied in other biotech wrangles.

"The opinion … is remarkably short given the complex legal and scientific questions that were raised; it fails to clarify in any meaningful way the difference needed to change natural material into man-made material that is eligible for patent protection," lamented Jeffrey Lewis, president of the American Intellectual Property Law Association.

Myriad quickly sought to put a positive spin on the outcome of its four-year legal battle to protect its patent rights, announcing that the Supreme Court had upheld its patent claims on cDNA. Although conceding that the justices had ruled that five of its claims covering isolated DNA were not patent eligible, the company said it had more than 500 valid claims in 24 different patents over its BRACAnalysis test.

Plaintiffs declare victory for their campaign against gene patents

"The court rightfully found that patents cannot be awarded for something so fundamental to nature as DNA," said PATPUB's Dan Ravicher. Sandra Park of the ACLU Women's Rights Project declared that the nine justices had struck down a major barrier to patient care and medical innovation. "Myriad did not invent the BRCA genes and should not control them," she said. "Because of this ruling, patients will have greater access to genetic testing and scientists can engage in research on these genes without fear of being sued. "

So what does the decision mean for biotechnology scientists? Opinion is divided. Some, such as Nobel prize-winning gene scientist John Sulston, believe that patents do little to stimulate research. Backing the lawsuit against Myriad in 2009, Dr. Sulston said that gene patents could have a "chilling impact on research, obstruct the development of new genetic tests, and interfere with medical care … rather than fostering innovation ".

Francis Collins, the director of the National Institutes of Health, followed up his elated "Woo Hoo!! " tweet on the day of the Supreme Court decision with a more measured response, calling the ruling a victory for those awaiting gene-based approaches to medical care. "The right to control exclusively the use of a patient's genes could have made it more difficult to access new tests and treatments that rely on novel technologies that can quickly determine the sequence of any of the estimated 20,000 genes in the human genome."

But Jim Greenwood, head of the US-based industry group BIO, said the decision represents "a troubling departure " from decades of judicial and USPTO precedent supporting the patentability of DNA molecules that mimic naturally-occurring sequences, adding that it could create business uncertainty for a broader range of biotechnology inventions.

That view was echoed by Courtenay Brinckerhoff of Foley & Lardner, who said that while the decision will have far-reaching and long-term implications for the biotech industry, the biggest immediate impact is the level of ambiguity it presents to scientists and their financial backers. "Although the Supreme Court seemed to draw a bright line between ‘naturally occurring DNA' and ‘cDNA', there are many other types of DNA constructs that are patented, such as short nucleotide probes and primers and iRNA constructs," she says. It is unclear whether or how Myriad will be applied to other areas of biotechnology, such as proteins and antibodies, or to other pharmaceutical products, such as new chemical entities isolated from natural sources. Answering those questions will take years, noted Ms. Brinckerhoff, as the US Patent Office, Federal Circuit and Supreme Court develop a body of law around Myriad. "In the meantime, innovators, competitors, and investors must make important business decisions without knowing whether these types of patents will be upheld. "

Ms. Brinckerhoff and other attorneys also argue that Myriad sets the US apart from its economic rivals when it comes to rules on patenting genes. The EPO, for example, will grant patents for inventions related to gene sequences as long as applicants can demonstrate the industrial application of the sequence. Australia, Canada and Japan have similar rules, allowing the patenting of human genes providing they are isolated and the patent application explains how the genes are useful.

These jurisdictional differences mean that patent-chasing scientists will need to revise their IP strategies in the US. Now that USPTO examiners will no longer grant patents for isolated genomic DNA, biotech companies are likely to turn to trade secrets to protect their investments (a development that challenges the promise of the patent system - that disclosure is rewarded with a temporary monopoly). Whether they can keep their secrets secret will depend largely on the ability of rivals to reverse engineer their discoveries. Biotech companies such as Myriad are also likely to guard more closely the valuable data they accumulate in the course of their research. Companies that already hold patents over genes will need to revisit their portfolios and consider abandoning patents rather than pay fees to maintain hollow IP rights. Businesses that have licensed-in patent rights may want to renegotiate the royalty rates.

But despite the challenges that the opinion has posed for the biotech industry, the company at the center of the ruling remains bullish. As patent owners and their lawyers mulled over the implications of the Court's decision, Myriad itself was busy preparing patent infringement lawsuits. Less than a month after the Supreme Court issued its opinion, the company sued two businesses that launched rival BRCA tests in June. It also watched as politicians called on the National Institutes of Health to use so-called march-in rights to force Myriad to license its BRACAnalysis patents. The battle over biotech is far from over.

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